19-4363416-G-C

Position:

• chr19-4363416-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003025.4(SH3GL1):​c.682C>G​(p.Gln228Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,459,942 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SH3GL1 NM_003025.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.52

Genes affected

SH3GL1 (HGNC:10830): (SH3 domain containing GRB2 like 1, endophilin A2) This gene encodes a member of the endophilin family of Src homology 3 domain-containing proteins. The encoded protein is involved in endocytosis and may also play a role in the cell cycle. Overexpression of this gene may play a role in leukemogenesis, and the encoded protein has been implicated in acute myeloid leukemia as a fusion partner of the myeloid-lymphoid leukemia protein. Pseudogenes of this gene are located on the long arm of chromosomes 11 and 17. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jan 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SH3GL1	NM_003025.4	c.682C>G	p.Gln228Glu	missense_variant	7/10	ENST00000269886.7	NP_003016.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SH3GL1	ENST00000269886.7	c.682C>G	p.Gln228Glu	missense_variant	7/10	1	NM_003025.4	ENSP00000269886.2
SH3GL1	ENST00000417295.6	c.538C>G	p.Gln180Glu	missense_variant	6/9	2		ENSP00000404568.2
SH3GL1	ENST00000598564.5	c.490C>G	p.Gln164Glu	missense_variant	7/10	2		ENSP00000470792.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1459942 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726220

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 2024

The c.682C>G (p.Q228E) alteration is located in exon 7 (coding exon 7) of the SH3GL1 gene. This alteration results from a C to G substitution at nucleotide position 682, causing the glutamine (Q) at amino acid position 228 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T;.;.
Eigen	Benign	0.14
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Benign	0.051	D
MetaRNN	Uncertain	0.43	T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.0	M;.;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.5	D;.;N
REVEL	Benign	0.22
Sift	Benign	0.036	D;.;T
Sift4G	Benign	0.096	T;T;T
Polyphen		0.050	B;.;.
Vest4		0.48
MutPred		0.56		Loss of MoRF binding (P = 0.0634);.;.;
MVP		0.54
MPC		0.47
ClinPred		0.89	D
GERP RS		4.7
Varity_R		0.51
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1972679390; hg19: chr19-4363413;